Polymorphonuclear leukocytes participate in the mediation of immunologically-induced inflammation and tissue injury (particularly Types II and III of Coombs and Gell) in man via interactions with immune complexes (Fc regions of IgG) and components of the complement system (C5a and the opsonic fragment of C3). Such interactions, even in the absence of phagocytosis, lead to selective discharge from leukocytes of lysosomal constituents as well as generation and release of oxygen-derived free radicals, prostaglandins and thromboxanes. The applicant proposes to test the hypothesis that these responses to immune stimuli are initiated and can be modulated at the level of the leukocyte plasma membrane. The applicant's preliminary studies of ligand binding to human leukocyte surface receptors, redistribution of ligand-receptor complexes, and activation of cell surface enzymes will be expanded in an attempt to determine the roles played by cyclic nucleotides, divalent cations, energy metabolism, microtubules and microfilaments in regulating these processes. Concurrently, attempts will be made to isolate and purify granule and surface membranes from human polymorphonuclear leukocytes. If such attempts are successful, it will be possible to determine not only the chemical nature of leukocyte membrane receptors for complement and immunoglobulins but also the subcellular localization of enzymes and substrates involved in the generation of oxygen-derived free radicals (e.g., superoxide anion) and thromboxanes. Finally, the applicant proposes to examine what effects, if any, products of "stimulated" leukocytes (particularly oxygen-derived free radicals and thromboxanes) may have on other cell types (e.g., platelets) which are involved in immunologically-induced inflammation and tissue injury. Information derived from these studies may not only provide insight into the pathogenesis of a variety of immunologically-mediated human diseases, but also may provide important clues to more rational forms of therapy.